Management of cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is a form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure as well as sudden cardiac death. It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practicing clinicians in the field on the role of immunosuppression and the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored.

Dilated cardiomyopathy: causes, mechanisms, and current and future treatment approaches.

Dilated cardiomyopathy is conventionally defined as the presence of left ventricular or biventricular dilatation or systolic dysfunction in the absence of abnormal loading conditions (eg, primary valve disease) or significant coronary artery disease sufficient to cause ventricular remodelling. This definition has been recognised as overly restrictive, as left ventricular hypokinesis without dilation could be the initial presentation of dilated cardiomyopathy. The causes of dilated cardiomyopathy comprise genetic (primary dilated cardiomyopathy) or acquired factors (secondary dilated cardiomyopathy). Acquired factors include infections, toxins, cancer treatment, endocrinopathies, pregnancy, tachyarrhythmias, and immune-mediated diseases. 5-15% of patients with acquired dilated cardiomyopathy harbour a likely pathogenic or pathogenic gene variant (ie, gene mutation). Therefore, the diagnostic tests and therapeutic approach should always consider both genetic and acquired factors. This Seminar will focus on the current multidimensional diagnostic and therapeutic approach and discuss the underlying pathophysiology that could drive future treatments aiming to repair or replace the existing gene mutation, or target the specific inflammatory, metabolic, or pro-fibrotic drivers of genetic or acquired dilated cardiomyopathy.

Current treatment and immunomodulation strategies in Acute Myocarditis.

Myocarditis is an inflammatory disease of the myocardium characterized by a great heterogeneity of presentation and evolution. Treatment of myocarditis is often supportive and the evidence for immunosuppression is scarce and debated. Conventional treatment is based on clinical presentation, ranging from conservative to advanced mechanical assist devices. In this setting, immunosuppression and immunomodulation therapies are mostly reserved for patients presenting with major clinical syndromes. In this review, we will summarise the current evidence and strategies for conventional and immunosuppressive treatments for patients presenting with acute myocarditis.

Results from the "Me & My Heart" (eMocial) Study: a Randomized Evaluation of a New Smartphone-Based Support Tool to Increase Therapy Adherence of Patients with Acute Coronary Syndrome.

PURPOSE: This study evaluated whether patient support, administered via an electronic device-based app, increased adherence to treatment and lifestyle changes in patients with acute coronary syndrome (ACS) treated with ticagrelor in routine clinical practice. METHODS: Patients (aged ≥ 18 years) with diagnosed ACS treated with ticagrelor co-administered with low-dose acetylsalicylic acid were randomized into an active group (with support tool app for medication intake reminders and motivational messages) and a control group (without support tool app), and observed for 48 weeks (ClinicalTrials.gov Identifier: NCT02615704). Patients were asked to complete the 36-item Short-Form Health Survey (SF-36) and Lifestyle Changes Questionnaire (LSQ), and were assessed for blood pressure and body mass index (BMI) at baseline (visit 1) and at the end of the study (visit 2). Medication adherence was measured using the Brilique Adherence Questionnaire (BAQ). RESULTS: Patients (N = 676) were randomized to an active (n = 342) or a control (n = 334) group. BAQ data were available for 174 patients in the active group and 174 patients in the control group. Over the 48-week period, mean (standard deviation) adherence for the active and control groups was 96.4% (13.2%) and 91.5% (23.1%), respectively (effect of app intervention, p < 0.05). There were no significant differences in blood pressure and BMI between visits. General improvements in SF-36 and LSQ scores were observed for both groups. CONCLUSION: The patient support tool app was associated with significant improvements in patient-reported treatment adherence compared with a data collection app alone in patients prescribed ticagrelor for ACS.

Leitlinie Myokarditis der Deutschen Gesellschaft für Pädiatrische Kardiologie.

This consensus statement presents updated recommendations on diagnosis and treatment of myocarditis in childhood.

Stabilin-1 mediates beneficial monocyte recruitment and tolerogenic macrophage programming during CVB3-induced viral myocarditis.

Pathological innate and adaptive immune response upon viral infection may lead to cardiac injury and dysfunction. Stabilin-1 is a scavenger receptor that regulates several aspects of the innate immunity. Whether stabilin-1 affects the inflammatory response during viral myocarditis (VM) is entirely unknown. Here, we assess the role of stabilin-1 in the pathogenesis of VM and its suitability as a therapeutic target. Genetic loss of stabilin-1 increased mortality and cardiac necrosis in a mouse model of human Coxsackievirus B3 (CVB3)-induced myocarditis. Absence of stabilin-1 significantly reduced monocyte recruitment and strongly reduced the number of alternatively activated anti-inflammatory macrophages in the heart, enhancing a pro-inflammatory cardiac niche with a detrimental T lymphocyte response during VM. Yeast two-hybrid screening, confirmed by affinity chromatography, identified fibronectin as a stabilin-1 interacting partner. Absence of stabilin-1 specifically decreased monocyte adhesion on extracellular fibronectin in vitro. Loss of Type III repeats Extra Domain A (EDA) of fibronectin during VM also increased the mortality and cardiac necrosis as in stabilin-1 knockout mice, with reduced monocytic cardiac recruitment and increased T lymphocyte response. Collectively, stabilin-1 has an immune-suppressive role of limiting myocardial damage during VM, regulating anti-inflammatory monocyte-recruitment to the site of inflammation.

The non-invasive assessment of myocardial work by pressure-strain analysis: clinical applications.

Pressure-volume (PV) analysis is the most comprehensive way to describe cardiac function, giving insights into cardiac mechanics and energetics. However, PV analysis still remains a highly invasive and time-consuming method, preventing it from integration into clinical practice. Most of the echocardiographic parameters currently used in the clinical routine to characterize left ventricular (LV) systolic function, such as LV ejection fraction and LV global longitudinal strain, do not take the pressure developed within the LV into account and therefore fall too short in describing LV function as a hydraulic pump. Recently, LV pressure-strain analysis has been introduced as a new technique to assess myocardial work in a non-invasive fashion. This new method showed new insights in comparison to invasive measurements and was validated in different cardiac pathologies, e.g., for the detection of coronary artery disease, cardiac resynchronization therapy (CRT)-response prediction, and different forms of heart failure. Non-invasively assessed myocardial work may play a major role in guiding therapies and estimating prognosis. However, its incremental prognostic validity in comparison to common echocardiographic parameters remains unclear. This review aims to provide an overview of pressure-strain analysis, including its current application in the clinical arena, as well as potential fields of exploitation.

Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies.

Described as the 'single largest unmet need in cardiovascular medicine', heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications-defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)-represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved 'epidrugs' (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF.

Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies.

Described as the 'single largest unmet need in cardiovascular medicine', heart failure with preserved ejection fraction (HFpEF) remains an untreatable disease currently representing 65% of new heart failure diagnoses. HFpEF is more frequent among women and associates with a poor prognosis and unsustainable healthcare costs. Moreover, the variability in HFpEF phenotypes amplifies complexity and difficulties in the approach. In this perspective, unveiling novel molecular targets is imperative. Epigenetic modifications-defined as changes of DNA, histones, and non-coding RNAs (ncRNAs)-represent a molecular framework through which the environment modulates gene expression. Epigenetic signals acquired over the lifetime lead to chromatin remodelling and affect transcriptional programmes underlying oxidative stress, inflammation, dysmetabolism, and maladaptive left ventricular remodelling, all conditions predisposing to HFpEF. The strong involvement of epigenetic signalling in this setting makes the epigenetic information relevant for diagnostic and therapeutic purposes in patients with HFpEF. The recent advances in high-throughput sequencing, computational epigenetics, and machine learning have enabled the identification of reliable epigenetic biomarkers in cardiovascular patients. Contrary to genetic tools, epigenetic biomarkers mirror the contribution of environmental cues and lifestyle changes and their reversible nature offers a promising opportunity to monitor disease states. The growing understanding of chromatin and ncRNAs biology has led to the development of several Food and Drug Administration approved 'epidrugs' (chromatin modifiers, mimics, anti-miRs) able to prevent transcriptional alterations underpinning left ventricular remodelling and HFpEF. In the present review, we discuss the importance of clinical epigenetics as a new tool to be employed for a personalized management of HFpEF.

Extracorporeal life support in patients with acute myocardial infarction complicated by cardiogenic shock - Design and rationale of the ECLS-SHOCK trial.

BACKGROUND: In acute myocardial infarction complicated by cardiogenic shock the use of mechanical circulatory support devices remains controversial and data from randomized clinical trials are very limited. Extracorporeal life support (ECLS) - venoarterial extracorporeal membrane oxygenation - provides the strongest hemodynamic support in addition to oxygenation. However, despite increasing use it has not yet been properly investigated in randomized trials. Therefore, a prospective randomized adequately powered clinical trial is warranted. STUDY DESIGN: The ECLS-SHOCK trial is a 420-patient controlled, international, multicenter, randomized, open-label trial. It is designed to compare whether treatment with ECLS in addition to early revascularization with percutaneous coronary intervention or alternatively coronary artery bypass grafting and optimal medical treatment is beneficial in comparison to no-ECLS in patients with severe infarct-related cardiogenic shock. Patients will be randomized in a 1:1 fashion to one of the two treatment arms. The primary efficacy endpoint of ECLS-SHOCK is 30-day mortality. Secondary outcome measures such as hemodynamic, laboratory, and clinical parameters will serve as surrogate endpoints for prognosis. Furthermore, a longer follow-up at 6 and 12 months will be performed including quality of life assessment. Safety endpoints include peripheral ischemic vascular complications, bleeding and stroke. CONCLUSIONS: The ECLS-SHOCK trial will address essential questions of efficacy and safety of ECLS in addition to early revascularization in acute myocardial infarction complicated by cardiogenic shock.

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.

Management of Myocarditis-Related Cardiomyopathy in Adults.

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

An optimized imaging protocol for [99mTc]Tc-DPD scintigraphy and SPECT/CT quantification in cardiac transthyretin (ATTR) amyloidosis.

BACKGROUND: In [99mTc]Tc-DPD scintigraphy for myocardial ATTR amyloidosis, planar images 3 hour p.i. and SPECT/CT acquisition in L-mode are recommended. This study investigated if earlier planar images (1 hour p.i.) are beneficial and if SPECT/CT acquisition should be preferred in H-mode (180° detector angle) or L-mode (90°). METHODS: In SPECT/CT phantom measurements (NaI cameras, N = 2; CZT, N = 1), peak contrast recovery (CRpeak) was derived from sphere inserts or myocardial insert (cardiac phantom; signal-to-background ratio [SBR], 10:1 or 5:1). In 25 positive and 38 negative patients (reference: endomyocardial biopsy or clinical diagnosis), Perugini scores and heart-to-contralateral (H/CL) count ratios were derived from planar images 1 hour and 3 hour p.i. RESULTS: In phantom measurements, accuracy of myocardial CRpeak at SBR 10:1 (H-mode, 0.95-0.99) and reproducibility at 5:1 (H-mode, 1.02-1.14) was comparable for H-mode and L-mode. However, L-mode showed higher variability of background counts and sphere CRpeak throughout the field of view than H-mode. In patients, sensitivity/specificity were ≥ 95% for H/CL ratios at both time points and visual scoring 3 hour. At 1 hour, visual scores showed specificity of 89% and reduced reader's confidence. CONCLUSIONS: Early DPD images provided no additional value for visual scoring or H/CL ratios. In SPECT/CT, H-mode is preferred over L-mode, especially if quantification is applied apart from the myocardium.

Propensity score-based analysis of 30-day survival in cardiogenic shock patients supported with different microaxial left ventricular assist devices.

BACKGROUND AND METHODS: Microaxial left ventricular assist devices are used increasingly for treating cardiogenic shock. We compared the short-term outcome of patients supported with different microaxial devices for cardiogenic shock. A retrospective propensity score-adjusted analysis was performed in cardiogenic shock patients treated with either the Impella CP (n = 64) or the Impella 5.0/5.5 (n = 62) at two tertiary cardiac care centers between 1/14 and 12/19. RESULTS: Patients in the Impella CP group were significantly older (69.6 ± 10.7 vs. 58.7 ± 11.9 years, p = .001), more likely in INTERMACS profile 1 (76.6% vs. 50%, p = .003) and post-C-reactive protein (CPR) (36% vs. 13%, p = .006). The median support time was 2.0 days [0.0, 5.3] in the CP group vs. 8.5 days [4.3, 15.8] in the 5.0/5.5 group (p < .001). The unadjusted 30-day survival was significantly higher in the Impella 5.0/5.5 group (58% vs. 36%, p = .021, odds ratio [OR] for 30-day survival on Impella 5.0/5.5 was 3.68 [95% confidence interval [CI]: [1.46-9.90]], p = .0072). After adjustment, the 30-day survival was similar for both devices (OR: 1.23, 95% CI: [0.34-4.18], p = .744). Lactate levels above 8 mmol/L and preoperative CPR were associated with a significant mortality increase in both cohorts (OR: 10.7, 95% CI: [3.45-47.34], p < .001; OR: 13.2, 95% CI: [4.28-57.89], p < .001, respectively). CONCLUSION: Both Impella devices offer a similar effect with regard to survival in cardiogenic shock patients. Preoperative CPR or lactate levels exceeding 8 mmol/L immediately before implantation have a poor prognosis on Impella CP and Impella 5.0/5.5.

[Heart failure with preserved ejection fraction as a model disease for the cardio-pulmonary-renal syndrome : Importance of visceral fat expansion as central pathomechanism]. / Herzinsuffizienz mit erhaltener Ejektionsfraktion als Modellerkrankung für das kardio-pulmo-renale Syndrom : Bedeutung der viszeralen Fettexpansion als zentraler Pathomechanismus.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with diverse underlying etiologies and pathophysiological factors. Obesity and type 2 diabetes mellitus (T2DM), diseases which frequently coexist, induce a cluster of metabolic and nonmetabolic signaling derangements, which promote induction of inflammation, fibrosis and myocyte stiffness, all representing hallmarks of HFpEF. In contrast to other HFpEF risk factors, obesity and T2DM are often associated with the formation of an enlarged visceral adipose tissue (VAT), which is a highly active endocrine organ that can sustainably exacerbate inflammation and fibrotic remodeling of myocardial, renal, and vascular tissues via various paracrine and vasocrine signals. An abnormally large epicardial adipose tissue (EAT) thus not only causes a mechanical constriction of the diastolic filling procedure of the heart but is also associated with an increased release of proinflammatory adipokines that trigger atrial fibrillation and impaired left ventricular contraction parameters. Obese patients with HFpEF therefore belong to a unique HFpEF phenotype with a particularly poor prognosis that could benefit from an EAT-oriented phenotype-specific intervention. In addition to statins and antidiabetic drugs such as metformin, glucagon-like peptide­1 (GLP-1) receptor agonists and sodium-glucose transporter 2 (SGLT-2) inhibitors could also play an important role.

Usefulness and clinical relevance of left ventricular global longitudinal systolic strain in patients with heart failure with preserved ejection fraction.

In recent years, several studies have shown the usefulness and clinical relevance of left ventricular global longitudinal systolic strain (GLS) in different cardiovascular diseases. In line with this, the role of GLS in patients with heart failure with preserved ejection fraction (HFpEF) has achieved great importance in this predominant form of heart failure in the last years. In this regard, GLS has shown to be not only a sensitive parameter to detect subtle myocardial abnormalities but also a parameter of clinical and prognostic relevance in patients with HFpEF. In this review, we analyze the current evidence concerning the clinical relevance of GLS in patients with HFpEF and we discuss the potential usefulness of GLS in this complex and heterogeneous condition for which so far no effective therapy exists.

Meta-analysis on the immunohistological detection of inflammatory cardiomyopathy in endomyocardial biopsies.

Meta-analysis on immunohistological (IHC) concepts for the detection of inflammatory cardiomyopathy (InfCM) in endomyocardial biopsies (EMB). We included 61 publications, with 10,491 patients (mean age 47.1 years; men 66%) who underwent EMB and IHC evaluation. The 460 control patients were devoid of IHC proof of InfCM. The mean IHC detection rate of InfCM was 50.8% (95% CI 47.7-53.8%; range 18.4-91.7%). A publication bias was excluded (Funnel Plot p = 0.4264). This IHC detection rate was significantly (p < 0.0001) higher compared to the histological detection of myocarditis according to the Dallas criteria (mean 8.04%; 95% CI 5.08-12.5%; subset of 3274 patients in 30 publications). However, 13 different diagnostic IHC criteria were described in the publications, with various thresholds of diverse phenotypes of quantified infiltrates, and endothelial expression of diverse cell adhesion molecules (CAM), quantified either visually or by digital image analysis (DIA). The comparison of IHC with cardiac magnetic resonance (CMR) data available in a subset of 13 publications with 1185 patients revealed a sensitivity for CMR of 69% (95% CI 58-79%), a specificity of 73% (95% CI 59-84%), and a ROC-AUC of 0.77 (95% CI 0.73-0.81). This meta-analysis encompassing 10,491 patients confirms a mean detection rate of InfCM in 50.8% of EMB, being significantly more sensitive compared to the histological Dallas criteria. IHC cannot be fully substituted by CMR. However, standardization of the diverse IHC markers and protocols seems pertinent, especially considering the published adverse prognostic impact of IHC-confirmed InfCM and its published suitability for the selection of candidates responding favorably to immunosuppression.

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use.

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction: insights from the MEDIA-DHF study (The Metabolic Road to Diastolic Heart Failure).

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.